MC4R Genetic Variants Influence Weight Change After Switching to INSTI ART in HIV

Overview

In a cohort of 529 persons with HIV switching to integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy, specific melanocortin-4 receptor (MC4R) gene variants were significantly associated with weight changes post-switch. These findings support a neuroendocrine mechanism contributing to INSTI-related weight gain.

Background

Weight gain is a recognized metabolic adverse effect in persons with HIV (PWH) initiating or switching to INSTI-based antiretroviral therapy (ART). While overt metabolic disturbances like dyslipidemia are less common with INSTIs, weight gain varies widely among individuals, suggesting genetic factors may influence this outcome. The melanocortin-4 receptor (MC4R) plays a key role in appetite regulation and body weight, with variants linked to obesity and drug-induced weight gain in other contexts. This study investigated associations between MC4R variants and weight change following a switch to INSTI-based ART.

Data Highlights

Key Findings

• Three MC4R gene variants showed statistically significant associations (P < .05) with weight change after switching to INSTI-based ART.
• 62% of participants were overweight or obese at the time of INSTI switch, indicating a high baseline prevalence of elevated BMI.
• Weight change associations persisted after adjusting for age, sex, ancestry, BMI, CD4+ count, and viral load.
• Findings support a neuroendocrine contribution to INSTI-related weight gain mediated by melanocortin signaling pathways.
• Previous studies link MC4R variants to obesity and antipsychotic drug-induced weight gain, reinforcing the pharmacogenetic relevance of MC4R in ART-associated weight changes.

Clinical Implications

Clinicians should be aware that genetic variation in MC4R may influence weight trajectories in PWH switching to INSTI-based ART. Understanding these genetic factors could guide personalized management strategies to mitigate weight gain risks. Further research may enable genetic screening to identify patients at higher risk for significant weight gain after ART modification.

Conclusion

This study identifies MC4R genetic variants as contributors to weight change following INSTI-based ART switch in persons with HIV, highlighting the role of melanocortin pathways in ART-associated metabolic effects. These insights advance understanding of host genetic influences on treatment-related weight gain.

References

1. ACTG Studies A5001 and A5322 -- Advancing Clinical Therapeutics Globally
2. European Medicines Agency Report 2021 -- Dolutegravir Inhibition of MC4R Binding
3. GWAS Catalog -- Obesity-Related Genetic Variants